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Page 2 of 10 Ruff et al. Hepatoma Res 2023;9:37 https://dx.doi.org/10.20517/2394-5079.2023.51

(ICCA) originates from the second-order bile ducts in the liver and is thought to differ from extrahepatic
[1]
CCA (ECCA) in underlying biology and behavior . Surgical resection with adjuvant capecitabine carries
the best hope of achieving long-term survival. Given the propensity to develop recurrent or metastatic
disease, patients who undergo curative intent surgery still only have a 5-year survival rate between 20%-40%
[2,3] .Furthermore, more than 80% of patients present with advanced or metastatic disease and are not
[4]
candidates for resection .
Based on results from the ABC-02 trial, the combination of gemcitabine and cisplatin is currently the
first-line chemotherapy for advanced CCA . Additionally, patients with ICCA may benefit from liver-
[5]
directed therapy (e.g., hepatic artery infusion pump, Yttrium-90 radioembolization) . In recent years,
[6]
neoadjuvant chemotherapy in combination with liver-directed therapy has been discussed for patients with
[7]
locally advanced disease in an attempt to downstage them to an operative candidate . Despite this, the 5-
year survival rate is only 5%-10% for patients with advanced disease . Overall, systemic therapy options are
[2,3]
[8]
limited for patients with CCA and often complicated by adverse events and drug resistance . Additionally,
no regimen has outperformed gemcitabine and cisplatin since the ABC-02 trial was published over a decade
ago. As such, the focus has shifted to the development of effective targeted therapies and
immunotherapy [9,10] .

Genetic profiling of CCA tumors has started to identify common mutations that can be targeted. Javle et al.
performed next-generation sequencing on 554 biliary tract cancers (BTC), including 412 ICCA, and
reported the most common genetic aberrations . The most common mutations in patients with ICCA
[11]
were cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B; 27%), tumor protein 53 (TP53; 27%), KRAS
(22%), AT-rich interactive domain-containing protein 1A (ARID1A; 18%), and isocitrate dehydrogenase 1
(IDH1; 16%). Weinberg et al. profiled 1,502 BTC (825 were ICCA) and found a higher rate of IDH1,
ubiquitin carboxyl-terminal hydrolase (BAP1), polybromo-1 (PBRM1), and fibroblast growth factor
receptor (FGFR) genetic aberrations in ICCA tumors . IDH1 has been identified as a promising target for
[12]
ICCA treatment. We herein review the role IDH mutations play in ICCA development, recent data for IDH
inhibitors in ICCA treatment, and the challenges within the field of targeted therapy for ICCA.

MOLECULAR PATHOGENESIS OF INTRAHEPATIC CHOLANGIOCARCINOMA
ICCA originates from the second-order bile ducts within the liver when the epithelial cells lining the bile
duct undergo malignant transformation. The molecular mechanism of cholangiocarcinoma has not been
completely elucidated. A persistent pro-inflammatory state combined with increased growth factors and bile
acids may lead to the accumulation of mutations in cholangiocytes and uncontrolled cell growth. The
delicate homeostasis of the liver’s immunotolerant microenvironment is disrupted, leading to
oncogenesis . Sia et al. found two transcriptomic profiles of ICCA through gene expression profiling: the
[13]
“inflammation” subtype and the “proliferation” subtype . In the inflammation subtype, there is activation
[14]
of immune-related signaling pathways and an overexpression of cytokines. In contrast, the proliferation
subtype is described as activation of oncogenic signaling pathways (e.g., RAS, MAPK, MET) and mutations
in KRAS and BRAF.

IDH1 molecular pathway
IDH in physiologic conditions
IDH exists in three isoforms: IDH1, IDH2, and IDH3. IDH1 expression is highest in hepatocytes, where it
plays a role in lipogenesis and maintenance of redox homeostasis. IDH2 expression is highest in cardiac
[15]
muscle cells but still expressed in hepatocytes . While mutations in IDH1 and IDH2 genes have been
found in 16% and 4% of patients with ICCA, respectively, they are not commonly seen in patients with